Sucralose composition and process for its preparation

ABSTRACT

The present invention provides an improved form of sucralose and a process for making it.

[0001] This application claims benefit from provisional patentapplication Serial No. 60/249,782 filed Nov. 17, 2000, which isincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to an improved form of sucralose and aprocess for making it.

[0003] BACKGROUND OF THE INVENTION

[0004] Sucralose (4,1′,6′-trichloro-4,1′,6′-trideoxy-galactosucrose) ahigh intensity sweetener made from sucrose, can be used in many food andbeverage applications. Sucralose, unlike many artificial sweeteners, canbe used in cooking and baking with no loss of sweetening power.

[0005] Sucralose is generally made following the procedures set forth inU.S. Pat. Nos. 4,362,869; 4,380,476; 4,801,700; 4,950,746; 5,470,969 and5,498,709. In all these procedures one of the final steps in thesynthesis is a deacylation followed by the crystallization of thesucralose. Laboratory scale methods for crystallizing sucralose havebeen described in U.S. Pat. Nos. 4,343,934; 5,141,860; 4,977,254;4,783,526; 4,380,476; 5,298,611; 4,362,869; 4,801,700; and 4,980,463. Asis described in many of these patents the deacylation of the sucraloseprecursor is performed in methanol with a catalytic amount of sodiummethoxide. After completion of deacylation the resulting sucralosesolution is contacted with an ion exchange resin to convert the residualsodium methoxide to methanol. The ion exchange resin is then removed andthe volatile solvents and reaction byproducts are removed byco-distillation with water, which results in a solvent switch to water.The mixture is decolorized by contacting with activated carbon. Thecarbon is removed to provide a decolorized sucralose solution suitablefor crystallizing sucralose. The sucralose solution is concentrated toabout 55 weight percent sucralose (at about 50° C.). The crystallizationis performed by reducing the temperature to about 22° C. and adding ofabout 2 percent sucralose seed crystals. The crystals that formed areseparated from the mother liquor by centrifugation then dried. Themother liquor that is separated from the crystals is added to the nextbatch just prior to decolorization.

[0006] Unfortunately, this process has a few drawbacks.The mother liquorcan become acidic over time. Additionally, the accumulation ofimpurities can interfere with the crystallization of sucralose,resulting in the need to periodically purge or discard the motherliquor. Crystalline sucralose, prepared as described above, generatesminute amounts of hydrochloric acid, which reduces the shelf life ofsucralose.

[0007] It is an object of the present invention to provide an improvedprocess for producing a more stable form of crystalline sucralose.

[0008] It is another object of the present invention to provide animproved crystalline sucralose composition that exhibits increasedstability.

SUMMARY OF THE INVENTION

[0009] We have discovered that addition of a buffer to the sucralosesolution before crystallization significantly increases the stability ofthe sucralose crystallized from it and also increases the stability ofthe mother liquors during processing.

[0010] We have also discovered that by keeping the pH of the sucralosecontaining crystallization solution in the range of from about pH 5.5 toabout pH 8.5 during the crystallization of sucralose the final stabilityof crystalline sucralose can be improved.

[0011] In another embodiment of the present invention, we have provideda stable crystalline sucralose product that does not develop an aceticacid odor upon storage.

[0012] In yet another embodiment of the present invention we haveprovided a process for the production of a stable crystalline sucraloseproduct that does not develop an acetic acid odor upon storage.

[0013] In a further embodiment of the present invention we have alsosurprisingly discovered that crystalline sucralose with residualmoisture content of from about 0.5 to about 10 percent by weight hasimproved stability.

[0014] In yet a further embodiment of the present invention we havediscovered a product comprising crystalline sucralose in a containerthat will maintain the moisture content. Preferably the container willhave moisture vapor transfer rate (MVTR) of not more than 0.25 gramwater/100 square inches of surface area/24 hours, when tested at 38° C.at 92 percent relative humidity.

[0015] These inventions and other inventions will be apparent to thoseskilled in the art from reading the following specification (includingthe Examples and Claims).

BRIEF DESCRIPTION OF THE FIGURE

[0016]FIG. 1 is a flow chart of one embodiment of the crystallizationprocess described herein. As illustrated in this embodiment an aqueoussucralose containing reaction mixture is contacted with the motherliquor and then transferred to the decolorizing tank. The mixture isthen filtered and concentrated. The concentrated sucralose containingsolution is transferred to a crystallizer, seeded, cooled and thecrystals of sucralose are separated from the mother liquor bycentrifugation. The sucralose crystals are then dried and packaged. Themother liquor is recycled to the beginning of this process.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Sucralose and the methods of making sucralose have been describedin numerous patents such as U.S. Pat. Nos. 4,801,700; 4,950,746;5,470,969 and 5,498,709 which are hereby incorporated herein byreference. Following the deacylation of the protected alcohol groups inthe synthesis of sucralose, the reaction mixture containing thesucralose needs to be neutralized, stabilized, decolorized and thesucralose removed from the mixture by crystallization.

[0018] The reaction mixture containing the sucralose can be neutralizedby a treatment to convert any residual methoxide present to methanol.Conventionally this is accomplished by the addition of an [H+] ionexchange resin. Suitable ion exchange resins are known in the art andinclude AMBERLITE® IRC50 [H+] (Rohm and Haas).

[0019] To facilitate concentration and further processing of theneutralized reaction mixture any residual volatile solvents or reactionproducts are removed by distillation. Preferably this distillation iscarried out under reduced pressure. To concentrate the neutralizedreaction mixture and water is added to obtain an aqueous solution thatcontains from about 30 to about 70 percent by weight sucralose,preferably from about 45 to about 65 percent by weight sucralose. Thereaction mixture is maintained at a temperature sufficient to keep thesucralose in solution. Generally the temperature will be from about 45°C. to about 50° C.

[0020] Before or after the neutralization of the sucralose containingsolution, it may be contacted with a decolorizing agent. Most commonlythe decolorizing agent will be an activated carbon, but otherdecolorization agents can also be used. The carbon may be in a powderform or packed in a column. However, the carbon must be removed from thesolution before crystallization. The amount of carbon used will dependon the amount of colorant in the reaction mixture and the type ofcarbon. Those skilled in the art can readily determine the minimumappropriate amount of carbon to add to decolorize the mixture. Thecarbon can be removed by conventional means (e.g. by filtration) ifadded in a loose form.

[0021] At this point a small amount of buffer salt is added to stabilizethe concentrated sucralose solution. A further adjustment to the pH isalso made to provide a neutral solution. The buffer can be any foodacceptable salts of food acceptable weak acids such as sodium orpotassium acetate, citrate, ascorbate, benzoate, caprylate, diacetate,fumarate, gluconate, lactate, phosphate, sorbate, tartrate and mixturesthereof. Preferred buffer include sodium acetate and sodium citratewhich can be used. In fact minute amounts of sodium acetate may bepresent as byproduct reactions insufficient to buffer thecrystallization. The neutralization can be accomplished using any pHadjusting acid or base compounds that will not be inconsistent with theuse of sucralose in food or compromise the taste of the final sucraloseproduct. Generally, the following pH adjusting compounds may be usedsodium, potassium, or other food acceptable salts of hydroxide,carbonate, bicarbonate acetate, citrate, ascorbate, benzoate, caprylate,diacetate, fumarate, gluconate, lactate, phosphate, sorbate, tartrateand mixtures thereof. A preferred pH-adjusting compound is sodiumhydroxide.

[0022] We have however discovered that it is advantageous to use smallamounts of sodium acetate such that the amount of sodium acetate in thecrystallization mother liquor is maintained at a concentration of lessthan 100 ppm (parts per million) and preferably less than 50 ppm andmost preferably from about 35 ppm to about 50 ppm to ensure that solidsucralose products do not develop an acetic acid odor.

[0023] During crystallization the pH of the sucralose containingsolution should be maintained in the range of about 5.5 to about 8.5 andpreferably about 6.5 to about 7.8 and most preferably about 7 to about7.8. Maintaining the pH in these ranges significantly enhances thelong-term stability of the sucralose product and the recycled motherliquors.

[0024] The sucralose may be crystallized from the sucralose containingsolution using conventional crystallization equipment. The aqueoussucralose solution is concentrated to about 55 percent by weightsucralose content the sucralose and is cooled to between about 10° C. toabout 30° C. and preferably between about 20° C. to about 25° C.Preferably to induce crystal formation the aqueous sucralose solution isseeded with sucralose seed. As a general guideline, seed crystalscomprising about 2 percent by weight of the sucralose in thecrystallization mixture appear to provide desirable crystal formation.

[0025] The crystals are separated from the mother liquor using acentrifuge or filter and the mother liquor is recycled to an earlierpoint in the process after neutralization and before crystallization.Preferably the mother liquor will be recycled and added to the reactionmixture after neutralization and before the decolorizing step.

[0026] The crystals may be washed to remove any residual mother liquorand dried using conventional drying equipment such as a tray orcompartment dryer, agitated tray vertical turbo dyer, agitated batchrotary dryer, fluidized bed dryer or pneumatic conveying dryer. Thedryer can be operated at atmospheric pressure or reduced pressure inbatch or continuous modes. Experiments have unexpectedly demonstratedthat sucralose stability is enhanced if the residual sucralose moisturecontent is in the range of about 0.5 to about 10 percent by weight andpreferably from about 0.5 to about 5 percent by weight and mostpreferably from about 0.5 to about 2 weight percent. The sucralosereferred to in this paragraph is non-hydrous meaning it does not containany significant amounts of sucralose hydrates (e.g. sucralosepentahydrate). If the sucralose is dried to a lower moisture content thesucralose is actually less stable. The temperature in the dryer shouldbe held below 60° C. and preferably in the range of about 35° C. toabout 45° C.

[0027] Ideally the moisture content of the final sucralose product willbe maintained during shipping and handling between about 0.5 to about 10percent by weight using a package that maintains the moisture content.The less permeable the material is the more moisture will be retainedand the more stable the product will be. Generally the packaging will bea container that will maintain the moisture content of the sucralose. Itis desired that the container have a moisture vapor transfer rate (MVTR)of not more than 0.25 gram water/100 square inches of surface area/24hours, when tested at 38° C. at 92 percent relative humidity. Preferablythe MVTR of the container will be not more than 0.2 grams/100 squareinches/24 hours. More preferably the MVTR of the container will be notmore than 0.15 grams/100 square inches/24 hours. Most preferably theMVTR of the container will be not more than 0.1 grams/100 squareinches/24 hours. The packaging can be flexible or rigid packaging.Suitable materials for making sucralose Packaging include but are notlimited to moisture limiting packaging such as metallized or aluminumfoil laminated substrates such as a polymer films or a kraft paper.Suitable polymers include but are not limited to polyolefins (such ashigh-density (linear) polyethylene, polypropylene, etc.), polyesters(such as polyalkyl terephthalates e.g. polyethylene terephthalate,polycyclohexane-1,4-dimethylene terephthalate, polybutyleneterephthalate, etc.), polyvinyl chloride, polyvinyl fluoride, andcopolymers of polyvinyl chloride and polyvinyl fluoride. Additionally,packaging materials that can be used including but not limited tomulti-walled paper bags having a suitable moisture barrier, fiber drumshaving polymeric or aluminum foil linings integral with the drum wall orloose liners inserts. Rigid containers such as blow molded drums andpails made of polymers with moisture barriers may also be used. Flexiblepackages such as shipping bags made of a polymer substrate arepreferred. Most preferred are bags made from aluminum foil laminated topolymer films formed from polymers that are commonly used to makemoisture resistant packaging (e.g. laminates of aluminum foil and thepolyolefins or polyesters listed above).

EXAMPLES

[0028] General Procedures

[0029] Preparing Samples for Accelerated Stability Testing

[0030] Label seven 6 oz. and seven 18 oz. WHIRLPAK® polyethylene bagswith indelible marker for each batch being tested for stability.Accurately weigh 25 g±0.01 g of sucralose into each 6 oz. WHIRLPAK®polyethylene bag. Heat or impulse seal the 6 oz. bag to ensure airtightness. Cut off any excess polyethylene at the top of bag above theseal. Place the 6 oz. sealed bag into the 18 oz. bag and neat or impulseseal the 18 oz. bag to ensure air tightness. Roll down the top of the 18oz. bag above the seal and bend the metal ties to form hooks.

[0031] Accelerated Stability Test

[0032] Place the prepared bags into an oven stabilized at 50° C.±0.5° C.by hanging them from racks by the bag hooks. The bags must be freelysuspended and not touch anything. Record the time samples are placedinto oven.

[0033] pH Stability

[0034] The pH stability test is conducted on the sucralose at time zero(the day the samples are placed in the oven, before the sucralose isexposed to elevated temperature) and every 24 hours until the batchbeing tested fails the test.

[0035] Preparation of pH Adjusted Water

[0036] Place approximately 100 ml of deionized water into a 150 mlbeaker. Using 0.1 N hydrochloric acid and/or 0.1 N sodium hydroxide,adjust the pH of the water to be between 5.8 and 6.0. Record the pHreading.

[0037] Preparation of the Sucralose Sample Solution

[0038] Accurately weigh 5 g±0.001 g of the product to be tested andtransfer it to a 50 ml volumetric flask. Dissolve and bring to the markby adding pH-adjusted water. If the sample to be tested is one that hasbeen exposed to heat, remove one bag of the batch being tested from theoven and allow it to cool to room temperature before opening andsampling.

[0039] Measure the pH

[0040] Pour the solution into a 100 ml beaker containing a stir bar, andslowly stir the solution on a magnetic stirrer. Immerse the pH electrodein the sample, allow the pH reading to stabilize and record the pHreading of the sample.

[0041] If no pH drop is observed after all the bags have been tested,the experiment is void and the test must repeated with a larger numberof bags.

[0042] Color Stability

[0043] Only a single sample need be used for this test. Prepare and heatthe double bag as described above. Visually inspect the contents of thesingle bag prepared for color stability every 24 hours. Record thenumber of days to first color development.

[0044] Calculations and Interpretations

[0045] pH Stability

[0046] Record (to one decimal place) the pH of both the pH-adjustedwater used, and the sample sucralose solution. Subtract the pH of thesample solution from that of the pH adjusted water. Report the result as(−) for a pH drop and (+) for a pH gain, e.g.: pH of pH adjusted water6.0 pH of sample 5.7 result −0.3

[0047] The sample fails the test if there is a pH drop of 1.0 pH unit ormore. The pH stability of the batch is defined as the number of daysuntil the pH drop between the sample solution and that of the pHadjusted water is ≧1.0.

[0048] Color Stability

[0049] The color stability of the batch is defined as the number of daysuntil the first color development is observed.

Example 1

[0050] Effect of Buffer Concentration in the Crystallization MotherLiquor on Product Stability

[0051] A number of batches of sucralose were prepared with varyingamounts of sodium acetate in the mother liquor and tested as above.RESULTS: Sodium Acetate Days to Sample (ppm) in the Initial Initial pHpH Number Mother Liquor pH difference Failure 1 >300 5.72 −0.20 6 2 >3005.73 −0.19 6 3 >300 5.44 −0.48 6 4 >300 5.64 −0.28 6 5 >300 5.64 −0.28 66 >300 5.53 −0.39 4 7 >300 5.70 −0.22 5 8 >300 5.19 −0.73 5 9 >300 6.19+0.23 7 10 >300 5.90 −0.05 5 11 >300 6.05 +0.10 6 12 >300 5.85 −0.10 613 >300 5.85 −0.10 5 14 35-50 5.95 +0.02 6 15 35-50 6.06 +0.13 5 1635-50 6.20 +0.27 6 17 35-50 6.03 +0.10 6 18 35-50 6.00 +0.07 6 19 35-506.06 +0.13 6 20 35-50 6.09 +0.08 6 21 35-50 6.05 +0.10 6 22 35-50 6.08+0.09 6 23 35-50 6.12 +0.13 5 24 35-50 6.02 +0.03 5 25 35-50 6.03 +0.056 26 35-50 6.06 +0.10 6 27 35-50 5.99 +0.03 6 28 35-50 6.00 +0.02 6 2935-50 6.09 +0.12 6 30 35-50 5.95 −0.02 5 31 35-50 6.03 +0.06 5

[0052] From the tabulated data it can be seen that the average pHstability (in days to failure) of the products crystallized from asolution containing >300 ppm sodium acetate is 5.6 days. The averageinitial pH of those sample solutions was 5.7, and the average pHdifference between the sample solution and the pH-adjusted water at timezero was −0.21 (pH drop). Several batches exhibited a mild to strongodor of acetic acid.

[0053] For those batches crystallized from a solution containing only 30to 50 ppm of sodium acetate, the number of days to failure was the same(average of 5.7 days). The average initial pH was 6.0., while theaverage pH difference at time zero was +0.08. None of those batches hadany acetic acid odor.

[0054] Conclusions

[0055] The optimum level of sodium acetate in solution during thecrystallization of sucralose is 35-50 ppm. This level proved to besufficient to maintain the pH during the crystallization at acceptablelevels. The stability of the final product was excellent and there wasno acetic acid odor in the product.

Example 2

[0056] Effect of PH During Crystallization on Product Stability

[0057] Regardless of the amount of acetate or other buffer substancepresent in the crystallization, the pH of the mother liquor has atendency to drop over time. Historically, the pH has ranged from about 3to about 4. We have now found that if the pH is adjusted to near neutralduring crystallization, the stability of the final product issignificantly enhanced. The following table records the stabilityresults of several batches where pH during crystallization was varied.Sample pH at Initial pH Days to pH Number Crystallizer differenceFailure 32 2.75 −0.90 3 33 2.97 −0.94 4 34 2.97 −1.03 3 35 6.28 +0.10 536 5.99 +0.04 5 37 5.99 −0.06 5 38 6.07 +0.17 6 39 6.07 −0.02 7 40 7.01+0.40 7 41 6.13 +0.40 5 42 6.34 +0.17 5 43 6.13 +0.29 5 44 7.11 −0.18 645 7.17 +0.17 7 46 8.05 +0.43 7

[0058] It evident from the data that controlling the pH at nearneutrality (from about 6 to about 8) significantly increases the averagestability under accelerated stability test conditions.

Example 3

[0059] Effect of Residual Moisture on the Stability of Sucralose

[0060] For several batches of sucralose, samples for acceleratedstability testing were removed at intermediate moisture level during thedrying process, and the test was performed on the partially driedproduct as well as the final dried product. Moisture levels weredetermined by the loss-on-drying (LOD) procedure. The results aretabulated in the table below. Final Initial Days to Product Days toSample Moisture pH Moisture pH Number Content (%) Failure Content (%)Failure 35 2.04 7 0.05 5 36 1.87 7 0.02 5 37 8.71 21 0.02 5 38 8.07 230.83 6 39 4.55 13 2.00 7 40 4.01 13 1.59 7 41 3.43 12 0.08 5 42 3.16 90.05 5 43 5.00 8 0.02 5

[0061] These results clearly show that dry product stability isproportional to residual moisture content. This was an unexpectedresult, since most crystalline products are much more stable when dry.

[0062] Summary

[0063] While the residual moisture level exhibits the largest influenceupon product stability, it is by no means the only important variable.It cannot overcome the effect of lack of pH control duringcrystallization, for example. This was demonstrated by the fact thatexperimental samples 32, 33 and 34, crystallized with no pH control,were actually less stable at intermediate moisture contents (3 to 5%)than they were at their final moisture levels (0.05, 0.11 and 0.21%,respectively).

Example 4

[0064] Use of Moisture Impermeable Containers for Sucralose Storage

[0065] Samples of sucralose were tested for stability using the aboveprocedures, but using bags of different moisture permeability. All otherexperimental details were the same. The TYVEK®/polyethylene bags arepermeable, whilst the WHIRLPAK® bags are less permeability. The A8080bags consist of a aluminum foil laminated to low density polyethylene,which makes it very impermeable to moisture. The results are recordedbelow. Sample PACKAGE MATERIAL INITIAL pH # MATERIAL PROPERTY MOISTURESTABILITY 24 FF 91 TYVEK ®/ Very 0.05% 4 days Polyethylene permeable 24WHIRLPAK ® Moderately 0.05% 5 days Polyethylene permeable 24 A8080Impermeable 0.05% 8 days 47 FF 91 TYVEK ®/ Very 0.24% 4 daysPolyethylene permeable 47 A8080 Impermeable 0.24% 33 days

[0066] Conclusion

[0067] By using impermeable packaging capable of retaining the moisturein the bag we were able to increase the stability of sucralose from 4days to 33 days in accelerated stability testing. There is a directcorrelation between the bag moisture permeability and product stability.It is clear that other moisture impermeable materials may be used topackage sucralose and achieve this improved stability.

What is claimed is:
 1. A process for the crystallization of sucralosefrom an aqueous solution comprising controlling the pH of said aqueoussolution so as to maintain the pH in the range of from about 5.5 toabout 8.5 during the formation of sucralose crystals.
 2. The process ofclaim 1 wherein a buffer is added to the aqueous solution containingsucralose.
 3. The process of claim 2 wherein the buffer is the foodacceptable salt of a weak acid.
 4. The process of claim 3 wherein thecation of the salt is selected from the group consisting of sodium,potassium and mixtures thereof.
 5. The process of claim 4 wherein theanion of the salt is selected from the group consisting of acetate,citrate, ascorbate, benzoate, caprylate, diacetate, fumarate, gluconate,lactate, phosphate, sorbate, tartrate and mixtures thereof.
 6. Theprocess of claim 3 where the buffer is sodium acetate.
 7. The process ofclaim 2 wherein the aqueous solution contains less than 100 ppm ofbuffer.
 8. The process of claim 2 wherein the aqueous solution containsless than 50 ppm sodium acetate.
 9. The process of claim 1 wherein theaqueous solution contains in the range of from about 35 ppm to about 50ppm sodium acetate.
 10. The process of claim 1 wherein during therecrystallization the sucralose solution is seeded with crystallinesucralose.
 11. The process of claim 1 wherein the pH of the solution isin the range of from about pH 6.5 to about pH 7.8.
 12. The process ofclaim 1 wherein the pH of the solution is in the range of from about pH7 to about pH 7.8.
 13. A process for the crystallizing sucralosecomprising (a) adjusting the pH of a sucralose containing solution to apH of from about 5.5 pH to about 8.5 pH; then (b) crystallizingsucralose crystals from the sucralose containing solution therebyproviding sucralose crystals and a mother liquor; (c) separating thesucralose crystals from the mother liquor; and (d) drying the sucralosecrystals.
 14. The process of claim 13 wherein the sucralose is dried toa moisture content of from about 0.5 to about 10 percent by weight. 15.The process of claim 13 wherein the sucralose containing solution isseeded with crystalline sucralose prior to crystallization.
 16. Theprocess of claim 13 wherein the pH of the sucralose containing solutionis adjusted to a pH in the range of from about pH 6.5 to about pH 7.8.17. Crystalline sucralose crystallized from an aqueous sucralosesolution having a pH in the range of from about pH 5.5 to about pH 8.5.18. Crystalline sucralose crystallized from an aqueous sucralosesolution having a pH in the range of from about pH 6.5 to about pH 7.8.19. Crystalline sucralose crystallized from an aqueous sucralosesolution having a pH in the range of from about pH 7 to about pH 7.8.20. Crystalline sucralose crystallized from an aqueous solutioncontaining less than 100 ppm sodium acetate.
 21. The crystallinesucralose of claim 17 wherein the sucralose is crystallized from anaqueous solution containing less than 50 ppm sodium acetate.
 22. Thecrystalline sucralose of claim 17 wherein the sucralose is crystallizedfrom an aqueous solution containing from about 50 ppm to about 35 ppmsodium acetate.
 23. A nonhydrous crystalline sucralose having a residualmoisture content of from about 0.5 to about 10 percent by weight. 24.The sucralose of claim 23 wherein the sucralose has a residual moisturecontent of from about 0.5 to about 5 percent by weight.
 25. Thesucralose of claim 24 wherein the sucralose has a residual moisturecontent of from about 0.5 to about 2 percent by weight.
 26. A productcomprising crystalline sucralose in a container that will have amoisture vapor transfer rate (MVTR) of not more than 0.25 gram of waterper 100 square inches of surface area in 24 hours, when tested at 38° C.at 92 percent relative humidity.
 27. The product of claim 26 wherein thesucralose has a moisture content of from about 0.5 to about 10 weightpercent.
 28. The product of claim 26 wherein the container is a sealedpolymeric bag.
 29. The product of claim 26 wherein the bag ismetallized.
 30. The product of claim 26 wherein the bag is made fromaluminum foil laminated to a polyolefin or polyester film.